T-cells initiate the immune response, mediate antigen-specific effector functions, and regulate the activity of other leukocytes by secreting cytokines. For the generation of a proper T-lymphocyte (T-cell) immune response, two signals must be provided to the T-cell by antigen presenting cells (APC). Antigen must be presented to the T-cell receptor (TCR) via a major histocompatibility complex (MC), in an event that determines specificity. T-cells can only recognize antigen presented on an APC. In addition to the antigen receptor, proper T-cell activation also requires the interaction of other cell-surface molecules on both the T-cell and the APC. These molecules, referred to as co-stimulatory molecules, consist of a receptor on the responding cell and a ligand present on the inducer cell. This antigen independent, co-stimulatory signal must be delivered by engagement of members of the B7 family on the APC with their receptors on T-cells. A productive immune response leads to proliferation, differentiation, clonal expansion, and effector functions. In the absence of the second, co-stimulatory signal, T-cells undergo a state of long-lasting antigen-specific unresponsiveness, termed anergy. Phase II clinical experiments have demonstrated that blocking one co-stimulation pathway is efficacious in the treatment of psoriasis (Abrams et al., 2000, J Exp Med 192:681-94, Abrams et at, 1999, J Clin. Invest, 103:1243-52) and rheumatoid arthritis (Kremer et al., 2003, New England Journal of Medicine 349:1907-15), indicating that this general strategy is a good target for immunomodulatory therapy.
A particular co-stimulatory B7 molecule, B7 related protein-1 (B7RP1), is a type 1 transmembrane protein with a signal sequence and extracellular domain at the amino-terminus, an extracellular domain comprising two Ig loops, a transmembrane domain, and a carboxy terminal intracellular domain (PCT Application Publication No, WO 00/46240). B7RP1 preferentially binds to ICOS (which stands for “inducible costimulator”; Yoshinga et al., 2000, Int. Immun. 12:1439-1447) expressed on the cell surface of T-cells. ICOS plays an important role in the production of both type 1 and type 2 cytokines by activated T-cells (Coyle et al., 2000, Immunity 13:95-105).
B7RP1 is the sole ligand expressed constitutively on APCs (Yoshinaga et al., 1999, Nature. 402:827-32), while ICOS is expressed only on activated T-cells (McAdam et al., 2000, Journal of Immunology 165:5035-40). B7RP1-dependent signaling is required for the activation of the effector (i.e. fully activated) T-cell, as well as its maturation from its naïve precursor (Dong et al., 2003, Journal of Autoimmunity, 21:255-60; Coyle et al., 2000, Immunity 13:95-105). Consequently, the B7RP1/ICOS interaction is required for proper T-cell-dependent recall immune responses (Dong et al., 2003, Journal of Autoimmunity 21:255-60).
Current attempts to interfere with the co-stimulatory T-cell pathway have focused primarily on co-stimulatory polypeptides that block T-cell activation only, but have not focused on activation and maturation. Consequently, these therapies provide general inhibition of T-cell function. In contrast, blocking the B7RP1/ICOS interaction provides a more specific inhibition of T-cell function by affecting only mature effector T-cells. Thus, blocking the B7RP1/ICOS interaction in a clinical setting is highly desirable because it would provide a more limited side-effect profile than co-stimulation therapies that block naïve T-cell activation only.